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At least 19 recordsLinked to original sources

PubMed1975

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

Amygdala↗

PubMed1986

A comparative study of the locomotor activity effects of apomorphine and the "atypical dopamine agonists" (piribedil and S3608).

Apomorphine and the "atypical dopamine agonists" (piribedil and S3608) dose dependently increase locomotor activity (LA) in rats. The LA effects of all 3 drugs are readily attenuated by pretreatment with pimozide or sulpiride. Reserpine pretreatment or bilateral 6-hydroxydopamine lesions of the nucleus accumbens (NAS) potentiates apomorphine-induced LA but attenuates piribedil- and S3608-induced LA. The latter suggests an indirect mode of action for piribedil and for S3608. However, piribedil and S3608 at concentrations up to 10(-4)M do not cause release or inhibition of 3H-dopamine uptake in synaptosomes prepared from the rat NAS. Sulpiride antagonism of apomorphine-induced LA is surmountable by increasing the dose of apomorphine. Antagonism of piribedil- or S3608-induced LA by sulpiride is not surmountable by increasing the dose of either of the "atypical dopamine agonists". Furthermore, pretreatment with either piribedil or S3608 substantially increases the peak LA inducible by apomorphine. The effects of simultaneous injections of piribedil and S3608 are, however, not additive. These findings suggest that the LA stimulant effects of piribedil and S3608 are mediated via receptors or systems which differ from the receptors involved in the mediation of apomorphine-induced LA.

Animals↗

PubMed1977

Femoral vasodilatation produced by piribedil (ET495) and its metabolite S584 in the hindleg of the dog.

On local injection into the innervated hindleg of the dog piribedil, like apomorphine, produced a vasodilatation blocked by haloperidol. S584, the catechol metabolite of piribedil, produced a vasodilatation which was not blocked by haloperidol. Neither propranolol nor atropine influenced the vasodilatation produced by piribedil or S584. Denervation of the hindleg abolished the responses to piribedil and S584. During the infusion of noradrenaline into the denervated hindleg, the responses to S584 reappeared but those to piribedil did not. It is concluded from these experiments that the vasodilatation produced by piribedil in the innervated hindleg of the dog, like that of apomorphine, is mediated by dopamine receptors and that the effect of piribedil cannot be explained by the formation of its catechol metabolite S584.

Animals↗

PubMed1978

Inhibitory effects of piribedil on adrenergic neurotransmission.

The effects of piribedil on responses to sympathetic stimulation were investigated in anaesthetized dogs. Piribedil (1 mg/kg i.v.) impaired the vasoconstrictor responses to lumbar sympathetic chain stimulation of the perfused hindlimb without changing the effects of noradrenaline. Piribedil (2 mg/kg i.v.) depressed the chronotropic responses to stimulation of the right anterior ansa and the inotropic response to stimulation of the left anterior ansa. Stimulation of the splanchnic nerve induced frequency dependent increases in systemic blood pressure. Piribedil antagonized this effect. Piribedil (1 mg/kg i.v.) attenuated the constrictor responses of the perfused mesenteric artery to postganglionic sympathetic stimulation and reduced the decreases in renal blood flow caused by stimulation of sympathetic renal nerves. The inhibitory efforts of piribedil were preferential on responses induced by low frequency stimulation of nerves. The hypertensive, vasoconstrictor and tachycardic effects of noradrenaline and tyramine were not affected. The effects of piribedil were reversed by haloperidol (0.5 mg/kg i.v.) or pimozide (0.2 mg/kg i.v.).

Animals↗

PubMed1975

Piribedil (ET 495) in the treatment of Parkinson's disease combined with amantadine or levodopa.

The further therapeutic benefit of piribedil when combined with amantadine or Levodopa was studied by a double-blind, cross-over trial in 15 patients with Parkinson's disease. A significant improvement at the 5 per cent level for akinesia, gait, speech disorder and facial expression occurred when piribedil was added to Levodopa; and a more highly significant improvement at the 1 per cent level for akinesia, facial expression and finger dexterity occurred with piribedil and amantadine. No significant improvement occurred for special timed tests. Improvement was associated with side effects in both groups of patients. Side effects occurred with both placebo and active piribedil. Only nausea during piribedil and Levodopa treatment reached statistical significance when compared with the placebo. Piribedil did not give rise to any haematological or biochemical complications. Our findings suggest that piribedil is of further therapeutic benefit when added to amantadine or Levodopa. It was suggested that the improvement which occurred together with amantadine could be due to the combined action of both drugs on dopamine receptors.

Aged↗

PubMed1992

Parkinson's disease: pathological mechanisms and actions of piribedil.

The cause of the degeneration of dopamine-containing cells in the zona compacta of the substantia nigra in Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) (via its metabolite MPP+) to destroy nigral dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total iron content of substantia nigra coupled to a generalised decrease in brain ferritin content. Piribedil is used in the symptomatic treatment of Parkinson's disease and is particularly effective against tremor. Piribedil (and its metabolites) acts as a dopamine D-2 receptor agonist. However, in our studies in contrast to other dopamine agonists, in vivo piribedil interacts with dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with Parkinson's disease the beneficial effects of piribedil may be limited by nausea and drowsiness. Indeed, in MPTP-treated primates piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral dopamine receptor antagonist domperidone prevents the unwanted effects and piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1975

The influence of piribedil (ET495) on components of locomotor activity.

Recent evidence suggests piribedil affects both cerebral NA neurones and DA neurones and receptors since it increases brain MOPEG-SO4, an observation confirmed presently. In the reserpinised mouse piribedil and apomorphine caused a reversal of akinesia, which was significantly enhanced by concurrent administration of clonidine. However, piribedil neither reduced nor increased the motor effects of apomorphine or L-DOPA in the reserpinised mouse, but slightly enhanced that of amphetamine. Phenoxybenzamine reduced the motor action of L-DOPA but had no effect on that of apomorphine or amphetamine. These results suggest piribedil has no significant NA receptor blocking or stimulating action in the reserpinised animal. They confirm the view that piribedil increases cerebral NA turnover due to a presynaptic action on NA neurones.

Amphetamine↗

PubMed1986

Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys.

Rhesus monkeys were surgically prepared with chronic intravenous catheters and allowed to self-administer the indirect dopamine (DA) agonist cocaine (0.03 or 0.1 mg/kg/inj) or the direct D2 agonist piribedil (0.1 or 0.2 mg/kg/inj) on a fixed-ratio 10 schedule of drug delivery during daily 2 hour experimental sessions. When responding was stable, they were injected IV with SCH 23390, a selective D1 antagonist (0.003-0.3 mg/kg, 30 min pre-session) or pimozide, a selective D2 antagonist (0.003-0.3 mg/kg, 2 hours pre-session). Intermediate doses of pimozide generally increased self-administration of cocaine or piribedil, though increases in piribedil self-administration were more reliable. In contrast, intermediate doses of SCH 23390 either did not affect or decreased cocaine and piribedil self-administration. High doses of each antagonist decreased the rate of self-administration of each compound and produced catalepsy. The selective increase in responding maintained by cocaine or piribedil following pimozide pretreatment suggests a role for a D2-like receptor in psychomotor stimulant self-administration.

Animals↗

PubMed1986

Presynaptic actions of piribedil on the cardiovascular system of the pithed rat.

The influence of piribedil on cardiovascular sympathetic responses has been studied in the pithed rat. Piribedil (0.3-1 mg kg-1) inhibited the increases of diastolic blood pressure induced by spinal cord electrical stimulation at the level Th5-L4. This effect was reversed by sulpiride (0.3 mg kg-1) but not by yohimbine (0.3 mg kg-1). The cardiovascular responses induced by noradrenaline were unaffected by piribedil (0.3-1 mg kg-1). However piribedil (0.3-1 mg kg-1) did not modify the heart rate increase induced by spinal cord electrical stimulation at the C7-Th1 level. These results suggest that piribedil inhibits the vascular sympathetic transmission in the pithed rat via stimulation of presynaptic dopamine receptors.

Animals↗

PubMed1985

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat.

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 micrograms) or apomorphine (5, 10 and 20 micrograms) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.

Animals↗

PubMed1992

Retinal dopaminergic receptor affinity and ocular pharmacokinetic profile of piribedil.

Binding studies on retinal dopamine receptors have revealed the existence of both D1 and D2 receptors. Human retina micro-autoradiographs confirm the distribution of dopaminergic receptors in the plexiform layers. Piribedil, a dopaminergic agonist, is able to bind to D2 receptors, while its metabolite (S584) preferentially displaces D1-specific radioligands. These results demonstrate that piribedil has a dopamine-like pharmacological profile including direct interaction with receptors. When instilled into the rabbit eye, piribedil penetrates rapidly and accumulates in the pigmented epithelia--the iris ciliary body and chorioretina--before being rapidly cleared. Macro-autoradiographs confirm this distribution and show the levels to be compatible with the affinity of piribedil for retinal dopaminergic receptors.

Animals↗

PubMed1977

Controlled telethermographic study of the peripheral vasoactivity of oral piribedil.

A single-blind crossover study was carried out in 10 subjects with a healthy arterial system to compare the effects of oral piribedil and placebo on the peripheral circulation. Using a telethermographic technique, skin temperature variations from baseline values were measured, at 15 minute intervals over a 2-hour period, after treatment with 3 x 20 mg piribedil tablets, after 1 x 50 mg piribedil in a sustained-release tablet formulation, and after placebo. In contrast to placebo, a vaso-active effect was observed afte piribedil administration on all but 3 occasions. Peak temperature changes appeared later after the sustained-release tablet. Side-effects of treatment were minimal and no significant changes were recorded in blood pressure.

Administration, Oral↗

PubMed1976

Piribedil: its synergistic effect in multidrug regimens for parkinsonism.

Piribedil, a dopamine agonist, was administered to 13 patients with long-standing Parkinson's disease whose major symptoms were not well controlled on levodopa, anticholinergics, alpha-methyldopa, amantadine, or a combination of these agents. Twelve of the 13 clearly benefited from the addition of Piribedil although side effects precluded long term use in two cases. Beneficial results were obtained by using a combination of Piribedil, levodopa, and anticholinergic drugs. Side effects (hallucinations, confusion, dyskinesias) were frequent, but were usually reversible by lowering the dosage of levodopa or the accompanying anticholinergic medication. The synergistic effect of Piribedil and other antiparkinsonian drugs emphasizes the need for careful titration of all available medications in difficult cases and demonstrates the usefulness of dopamine receptor stimulators when drugs acting presynaptically have failed.

Aged↗

PubMedDate not supplied

The effect of piribedil on body temperature in mice and rats.

Piribedil produces a pronounced hypothermia both in mice and rats. This hypothermia was prevented by previous administration of dopamine receptor blocking agents (spiperone in mice and rats, pimozide in mice), tricyclic antidepressant drugs (imipramine, clomipramine, desipramine) in mice and LSD in rats. Administration of agents acting on serotonin receptors (cyproheptadine, p-chlorophenylalanine) or of a classical anticholinergic drug, atropine, did not change the hypothermizing effect of piribedil in rats. Thus, the hypothermia produced by piribedil is apparently similar to that produced by apomorphine. The possibility of a secondary stimulation of serotonergic receptors through direct stimulatory action of piribedil on dopamine neurons is discussed.

Animals↗

PubMed1975

Drug interactions with dopamin-stimulated adenylate cyclasses of caudate nucleus and retina: direct agonist effect of a piribedil metabolite.

Dopamine- and apomorphine-stimulated adenylate cyclase activity, which is antagonized by neuroleptic drugs (pimozide, fulphenazine, chlorpromazine, haloperidol), is present in caudate nucleus and retina of several mammalian species. The presence of abeta-OH group in a catecholamine agonist decreases maximal efficacy without altering sensitivity in the cebus monkey caudate system, whereas only sensitivity is decreased in the bovine retinal system (Brown and Makman, 1972). The presence of N-methyl or N-isopropyl or even the more extensive side chain modification and N-substitution present in S 584 has little or no effect on sensitivity or maximal response in monkey caudate. Such features result in major species differences in response to agents such as IPNE. The potent direct stimulatory effect of S 584 but not of piribedil on adenylate cyclase, the indirect stimulation of cyclase by preincubation of intact caudate with piribedil, and the effect of piribedil on cAMP content of intact caudate suggest the following mode of action of piribedil: conversion in the caudate to a catechol metabolite (S 584), which in turn stimulates the postsynaptic adenylate cyclase system.

Adenylyl Cyclases↗

PubMed1975

Cholinergic-dopaminergic interaction in the striatum: the effect of 6-hydroxydopamine or pimozide treatment on the increased striatal acetylcholine levels induced by apomorphine, piribedil and d-amphetamine.

Apomorphine (1 and 2 mg/kg), piribedil (15 and 60 mg/kg) and d-amphetamine (5 and 10 mg/kg) increased rat striatal acetylcholine levels without affecting choline. Pretreatment with pimozide (0.5 mg/kg) completely antagonized the effect of apomorphine and piribedil and by itself markedly decreased striatal acetylcholine levels. d-Amphetamine signigicantly antagonized the effect of pimozide. Nine days after pretreatment with 6-hydroxydopamine plus pargyline, striatal dopamine was decreased by 78% while acetylcholine and choline levels remained unaltered. Under these conditions, the effect of d-amphetamine was completely abolished while apomorphine and piribedil were just as active as in the vehicle-treated group. The results suggest that d-amphetamine acted indirectly to increase striatal acetylcholine levels probably through the release of dopamine and/or noradrenaline, while apomorphine and piribedil acted directly at dopamine receptor sites.

Acetylcholine↗

PubMed1992

Effect of a dopaminergic agonist, piribedil (Trivastal 50 mg LP), on visual and spatial integration in elderly subjects.

Dopamine acts as a neuromodulator in the retina. Dopaminergic deficiency of any origin, as observed in elderly subjects, is associated with altered visual performances, and more specifically with altered perception of contrasts. The goal of this study was to compare contrast vision in elderly subjects and young subjects (first phase, n = 20), then to compare this function in elderly subjects before and after 3 months of treatment with a dopaminergic agonist, piribedil (Trivastal 50 mg LP), administered once daily (second phase, n = 20). The perception of contrast was analysed using a test measuring sensitivity to colour contrast yielding threshold values for sensitivity to contrast in eight spatial frequencies and three colours (red, green, blue) and in two directions (horizontal and vertical). The results of the first phase of the study demonstrated that elderly subjects showed a decrease in contrast perception in comparison with young subjects, primarily in the high frequency range, and over the full range of stimulation for direction and colour. In the second phase, elderly subjects, in comparison with young subjects, showed altered visual contrast, again in the high frequency range, but also in the low frequency range for horizontal simulation with red and blue. After 3 months of treatment with piribedil the mean contrast sensitivity threshold, over the entire frequency range, had significantly increased (P less than 0.05) for all stimulations, apart for red in the vertical direction. These results underline the value of treatment with a dopaminergic agonist, piribedil in visual disturbances in patients with dopaminergic deficiency (Parkinson patients or elderly subjects).

Aged↗

PubMed1978

[Effect of piribedil on nocturnal sleep (author's transl)].

Piribedil, a dopamine agonist, was administered to 5 normal male subjects for two weeks. During the first two nights there was a reduction of about 17 p. 100 in paradoxical sleep (PS) and an increase of about 13 p. 100 in slow sleep II. There was a 15 p. 100 increase in PS during the third night. This increase is maintained for 8 nights in 3 subjects and 13 nights in 2 subjects. Other sleep parameters were not altered. Piribedil appears to give the impression of satisfactory sleep by reducing the subjective period before falling asleep. Piribedil also diminishes the remembrance of dreams.

Adult↗